Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

• the present invention relates to a pharmaceutical composition in the form of an eye drop formulation comprising enavogliflozin. More specifically, the present invention relates to a pharmaceutical composition in the form of an eye drop formulation, comprising enavogliflozin or a pharmaceutically acceptable salt thereof as an active ingredient; and a combination of specific surfactants, which provides excellent stability and increased intraocular exposure.
• Enavogliflozin which has a chemical structure of the following Chemical Formula 1, has inhibitory activity against SGLT2 (sodium-dependent glucose cotransporter 2) present in the intestines and kidneys and thus can be usefully used in the treatment of metabolic disorders, especially diabetes ( WO 2012/165914 , WO 2017/217792 , etc.).
• SGLT2 sodium-dependent glucose cotransporter 2
• a SGLT2 inhibitor including enavogliflozin or a pharmaceutically acceptable salt thereof has excellent preventive or therapeutic activity against diabetic eye diseases (e.g., diabetic retinopathy) ( Korean Laid-open Publication No. 10-2022-0079480 ). And, the present inventors have found that a SGLT2 inhibitor including enavogliflozin or a pharmaceutically acceptable salt thereof has excellent preventive or therapeutic activity against macular degeneration ( Korean Laid-open Publication No. 10-2023-0007963 ).
• Enavogliflozin has low water solubility, which makes it difficult to formulate into an aqueous solution form, for example, to an eye drop formulation in the form of an aqueous solution.
• Korean Laid-open Publication Nos. 10-2022-0079480 and 10-2023-0007963 disclose examples of the eye drop formulations in which enavogliflozin is solubilized by using polyoxyl 35 castor oil (Kolliphor TM ELP) and polysorbate 80 (Tween TM 80) as solubilizing agents.
• intraocular drug delivery is required for the treatment of posterior segment eye diseases such as diabetic retinopathy and macular degeneration.
• a drug in order for a drug to reach a disease site (e.g., the retina), it is necessary not only to effectively solubilize the drug, but also to increase the intraocular drug exposure by allowing the solubilized drug to penetrate through the cornea or conjunctiva and reach the retina.
• a formulation e.g., eye drop formulations.
• the present inventors have found that the conventional enavogliflozin-containing eye drop formulations (e.g., the eye drop formulations disclosed in Korean Laid-open Publication Nos. 10-2022-0079480 and 10-2023-0007963 ) exhibit significantly reduced stability upon long-term storage and do not provide satisfactory intraocular exposure.
• the present inventors carried out various formulation studies. As a result, the present inventors have found that, when formulation is performed using a combination of specific surfactants, the physical and chemical stabilities of enavogliflozin-containing eye drop formulations are remarkably increased.
• the present inventors have found that the combination of specific surfactants functions not only as a solubilizing agent but also as a stabilizing agent in an enavogliflozin-containing eye drop formulation.
• the present inventors have found that an eye drop formulation obtained by using the combination of specific surfactants can provide excellent pharmacological activity by significantly increasing the intraocular exposure of enavogliflozin.
• a pharmaceutical composition in the form of an eye drop formulation comprising enavogliflozin or a pharmaceutically acceptable salt thereof and the combination of specific surfactants.
• a pharmaceutical composition in the form of an eye drop formulation comprising enavogliflozin or a pharmaceutically acceptable salt thereof as an active ingredient; and a combination of polysorbate and polyoxyl 40 stearate as a solubilizing agent and a stabilizing agent.
• the enavogliflozin or a pharmaceutically acceptable salt thereof may be present at a concentration of 0.1 ⁇ 10 w/v%, preferably 0.3 ⁇ 8 w/v%, more preferably 0.5 ⁇ 5 w/v%.
• the combination of polysorbate and polyoxyl 40 stearate may be present at a concentration of 1 ⁇ 15 w/v%, preferably 4 ⁇ 10 w/v%.
• a weight ratio of polysorbate and polyoxyl 40 stearate may be 1 : 1 ⁇ 10, preferably 1 : 2 ⁇ 8.
• the pharmaceutical composition of the present invention may form nanomicelles having an average particle diameter of 1 ⁇ 500 nm, preferably 5 ⁇ 50 nm.
• the pharmaceutical composition of the present invention may further comprise at least one excipient selected from the group consisting of a penetration enhancer, a tonicity-adjusting agent, and a pH-adjusting agent.
• the penetration enhancer may be D- ⁇ -tocopheryl polyethylene glycol succinate.
• the tonicity-adjusting agent may be glycerin.
• the pharmaceutical composition of the present invention may have an osmolality of 230 to 350 mOsmol/kg and/or a pH of pH 6.0 ⁇ pH 7.5.
• the pharmaceutical composition in the form of an eye drop formulation according to the present invention comprises a combination of specific surfactants, i.e., a combination of polysorbate and polyoxyl 40 stearate, which makes it possible to increase the physical and chemical stabilities. Therefore, it has been found by the present invention that the combination of polysorbate and polyoxyl 40 stearate functions not only as a solubilizing agent but also as a stabilizing agent.
• the pharmaceutical composition according to the present invention which comprises said combination of specific surfactants, can provide excellent pharmacological activity by significantly increasing the intraocular exposure of enavogliflozin.
• the present invention provides a pharmaceutical composition in the form of an eye drop formulation, comprising enavogliflozin or a pharmaceutically acceptable salt thereof as an active ingredient; and a combination of polysorbate and polyoxyl 40 stearate as a solubilizing agent and a stabilizing agent.
• the pharmaceutical composition of the present invention may comprise the enavogliflozin or a pharmaceutically acceptable salt thereof in an amount suitable for the treatment of posterior segment eye diseases such as diabetic retinopathy and macular degeneration.
• the enavogliflozin or a pharmaceutically acceptable salt thereof may be present at a concentration of 0.1 ⁇ 10 w/v%, preferably 0.3 ⁇ 8 w/v%, more preferably 0.5 ⁇ 5 w/v%, in the pharmaceutical composition.
• the present invention when formulation is performed using a combination of specific surfactants, i.e., a combination of polysorbate and polyoxyl 40 stearate, the physical and chemical stabilities of enavogliflozin-containing eye drop formulations can be remarkably increased.
• the pharmaceutical composition of the present invention which comprises said combination of specific surfactants, can provide excellent pharmacological activity by significantly increasing the intraocular exposure of enavogliflozin.
• the polysorbate may be polysorbate 20, 40, 80, etc., and preferably polysorbate 80.
• the polyoxyl 40 stearate is also referred to as polyethylene glycol monostearate.
• the combination of polysorbate and polyoxyl 40 stearate may be present at a concentration of 1 ⁇ 15 w/v%, preferably 4 ⁇ 10 w/v%, in the pharmaceutical composition.
• a weight ratio of polysorbate and polyoxyl 40 stearate may be 1 : 1 ⁇ 10, preferably 1 : 2 ⁇ 8.
• the polysorbate may be present at a concentration of 0.1 ⁇ 10 w/v%, preferably 1 ⁇ 4 w/v%, in the pharmaceutical composition; the polyoxyl 40 stearate may be present at a concentration of 0.1 ⁇ 10 w/v%, preferably 3 ⁇ 7 w/v%, in the pharmaceutical composition, within the weight ratio in the above.
• the pharmaceutical composition of the present invention comprises the combination of polysorbate and polyoxyl 40 stearate and thus forms nanomicelles having an average particle diameter of 1 ⁇ 500 nm, preferably 5 ⁇ 50 nm.
• the pharmaceutical composition of the present invention may comprise excipients conventionally used in the field of eye drop formulations.
• the pharmaceutical composition of the present invention may further comprise at least one excipient selected from the group consisting of a penetration enhancer, a tonicity-adjusting agent, and a pH-adjusting agent.
• the penetration enhancer may be D- ⁇ -tocopheryl polyethylene glycol succinate (TPGS), which may be present e.g., at a concentration of 0.1 ⁇ 0.5 w/v%.
• the tonicity-adjusting agent may be glycerin, which may be present e.g., at a concentration of 0.5 ⁇ 6 w/v%.
• the pharmaceutical composition of the present invention may have an osmolality of 230 to 350 mOsmol/kg and/or a pH of pH 6.0 ⁇ pH 7.5.
• a pharmaceutical composition comprising 0.5 ⁇ 5 w/v% of enavogliflozin or a pharmaceutically acceptable salt thereof; 4 ⁇ 10 w/v% of the combination of polysorbate and polyoxyl 40 stearate; 0.1 ⁇ 0.5 w/v% of D- ⁇ -tocopheryl polyethylene glycol succinate; 0.5 ⁇ 6 w/v% of glycerin; and a pH-adjusting agent, in an aqueous medium, and forming nanomicelles having an average particle diameter of 5 ⁇ 50 nm.
• a weight ratio of polysorbate and polyoxyl 40 stearate may be 1 : 2 ⁇ 8.
• Example 1 Formulation Study - 1
• each excipient was dissolved in 5 mL of purified water at the maximum concentration recommended by the FDA (Table 2) and then enavogliflozin was added thereto until it was no longer dissolved, followed by stirring for approximately 12 hours. After confirming no dissolution after 12 hours, each sample was centrifuged at 4000 rpm for 30 minutes and the clear supernatant (1 mL) was taken and then diluted with methanol. The resulting solution was filtered through a 0.45 ⁇ m RC membrane filter. The first 2 mL was discarded and then the filtrate was used as a test solution.
• the surfactants Tween TM 80 and Kolliphor TM EL were selected as excipients for solubilizing enavogliflozin.
• the target concentration of enavogliflozin in an eye drop formulation is 0.5 to 5.0 w/v%, but the saturation solubility does not reach said concentration. Therefore, the two components having the best solubility were mixed and the saturation solubility of the active ingredient was measured according to the ratios thereof.
• Tween TM 80 and Kolliphor TM EL were mixed in the ratio shown in Table 3 below. The resulting mixture was heated to 40°C and then enavogliflozin was dissolved by adding thereto in a certain amount. The point at which enavogliflozin was no longer dissolved and the appearance thereof becomes cloudy was defined as a saturation solubility.
• Table 3 Surf mix-1 Surf mix-2 Surf mix-3 Surf mix-4 Tween TM 80 0.33% 1.0% 1.5% 2.0% Kolliphor TM EL 0.66% 2.0% 3.0% 4.0% Total concentration of surfactants (%) 1.0 3.0 4.5 6.0
• the saturation solubility was analyzed by adding the amounts of enavogliflozin dissolved up to the point where the appearance was maintained. As can be seen from the results of FIG. 1 , the solubility of enavogliflozin increased proportionally as the total concentration of surfactants increased and the surfactants need to be used at a concentration of at least 5.0 w/v% for dissolving to the target concentration of 5.0 w/v%.
• enavogliflozin-containing eye drop formulations (Formulation-1: 5.0 w/v% and Formulation-2: 2.0 w/v%) were prepared according to the components and amounts of Table 4 below.
• Tween TM 80 and Kolliphor TM EL were used as surfactants and TPGS was used as a penetration enhancer, and glycerin was used as a tonicity-adjusting agent.
• the excipients Tween TM 80, Kolliphor TM EL, glycerin, anhydrous sodium dihydrogen phosphate, and sodium hydroxide
• water for injection were heated to about 40°C under stirring (Dissolution-1 step).
• the active ingredient (enavogliflozin) was added thereto and heated to approximately 80°C (Dissolution-2 step). The solution was then cooled to 25°C and filtered through a 0.2 ⁇ m RC, PTFE, or PVDF membrane filter (Filtration step). Each obtained eye drop formulation was filled into a polyethylene tube.
• the membrane filter made of RC, PTFE, or PVDF as a filter material was used for filtration and the contents of the active ingredient before and after filtration were analyzed by HPLC in the same manner as in (1) above to confirm whether the active ingredient was adsorbed on the filter.
• the results are shown in Table 5 below.
• Table 5 Filter material Before filtration (%) After filtration (%) Adsorption rate (%) Formulation-1 RC 98.9 98.8 0.1 PTFE 98.5 0.4 PVDF 98.9 0.0 Formulation-2 RC 101.7 102.0 -0.3 PTFE 101.9 -0.2 PVDF 101.3 0.4
• the active ingredient did not show significant adsorption regardless of the filter material of the filter used in the filtration step and the most conventionally used RC material was selected as a filter for filtration step.
• the osmolality of Formulation-1 slightly exceeded the target criteria and thus it would be required to control the amount of tonicity-adjusting agent. Although the osmolality of Formulation-1 did not meet the target criteria, it was used as a sample in Formulation Study - 2 of Example 2 to observe the tendency of degradation products.
• the eye drop formulations were prepared using the same method as (3-1) of Example 1 (filtration using an RC membrane filter) according to the components and amounts of Table 7, with the active ingredient in the concentrations of 1.0 w/v%, 3.0 w/v%, and 5.0 w/v%, respectively.
• the eye drop formulation with 1.0 w/v% of the active ingredient would be sufficient in terms of saturation solubility, it was prepared by reducing the amount of surfactants by 30%.
• the amounts of the pH-adjusting agent and the tonicity-adjusting agent was adjusted so as to be suitable for the pH or the osmolality criteria (Table 7).
• Tween TM 80 and Kolliphor TM EL which are the solubilizing agents used for achieving the target concentration of active ingredient (i.e., enavogliflozin,) form micelles at a concentration above the critical micelle concentration. Since the formation of micelles or nanomicelles may affect the efficiency of drug delivery, we investigate whether the formulations of Formulation-3, Formulation-4, and Formulation-5 were form nanomicelles.
• the particle size distribution formed in the solution was analyzed using dynamic light scattering (DLS). The zeta potential was also measured to confirm the charge formed on the particle surface.
• the ELSZ -2000 of Otsuka was used as a DLS measurement instrument and the measurement was carried out under the conditions shown in Table 9 below.
• Table 9 Particle size distribution Zeta potential Cell type Disposable cell Flow cell Diluent Water Water Temperature (°C) 25.0 25.0 Analytical method Marquardt Smoluchowski
• the average particle size (Z-average) ranged from 11.9 ⁇ 29.4 nm and showed a tendency to increase as the ratio of the active ingredient increased.
• No. of distribution all formulations showed particle sizes of less than 10 nm.
• the zeta potential was found to have a weak negative charge.
• Table 11 The results obtained by evaluating the stability of Formulation-2 containing the combination of Kolliphor TM EL and Tween TM 80, while storing under an accelerated condition and under a room temperature condition for 2 months and for 4 months, are as shown in Table 11 below.
• Table 11 Initial 2 Months at room temperature 4 Months at room temperature 2 Months under accelerated condition 4 Months under accelerated condition Appearance Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid Content 99.0% 96.8% 86.6% 64.8% 60.2% Total degradation product 0.11% 0.26% 0.24% 0.12% 0.58% Suitability Suitable Suitable Unsuitable Unsuitable Unsuitable Unsuitable
• Formulation-2 was unsuitable as it exhibited precipitation or a content below the standard criteria in the stability tests conducted at the room temperature condition for 4 months, under the accelerated condition for 2 months, and under the accelerated condition for 4 months.
• a decrease in content occurs due to degradation of the active ingredient, the amount of degradation products increases significantly.
• the increase in degradation products derived from enavogliflozin was not significant.
• solubility of poorly soluble enavogliflozin was improved by using the surfactants, there would be a possibility that the interaction between the active ingredient and the surfactants may affect the stability during the storage thereof. Therefore, it can be indirectly evaluated by measuring the cloud point that solubility rapidly decreases when the water-soluble group in a nonionic surfactant is dehydrated upon heating. The reason for instability of the formulations was thus investigated and further formulation study involving the modification of solubilizing agents was carried out in order to stabilize the formulations.
• Polyoxyl 40 stearate (Myrj TM S40) was dissolved in 5 mL of purified water at the concentration of 7.0 w/v% and then enavogliflozin was added thereto until it was no longer dissolved, followed by stirring for approximately 12 hours. Thereafter, the degree of solubilization was evaluated in the same manner as in Example 1.
• the cloud point was measured by observing in naked eyes the point at which the appearance became opaque while gradually heating the test formulations.
• 5 mL of the test formulations i.e., the formulations of Formulation-6, Formulation-7, and Formulation-8 prepared in (2-3) below and the formulation of Formulation-1 was placed in a transparent glass vial and then stirred in a water bath while increasing the temperature by 0.5°C each time.
• the temperature at which the appearance of the formulation was changed from a clear and transparent liquid to a turbid suspension was taken as a cloud point.
• the eye drop formulations were prepared using the same method as (3-1) of Example 1 according to the components and amounts of Table 12, with the active ingredient in the concentrations of 1.0 w/v%, 3.0 w/v%, and 5.0 w/v%, respectively.
• Table 12 Raw material Formulation-6 (Active ingredient: 1.0 w/v%)
• Formulation-7 Active ingredient: 3.0 w/v%)
• Formulation-8 Active ingredient: 5.0 w/v%) Amount (mg/mL) Amount (mg/mL) Amount (mg/mL) Active ingredient Enavogliflozin 10.0 30.0 50.0
• Penetration enhancer TPGS 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 To
• Kolliphor TM EL can be used at a concentration of up to 5.0 w/v% and polyoxyl 40 stearate can be used at a concentration of up to 7.0 w/v%, for the route of ophthalmic administration. Based on these, the results obtained by comparing the solubilizing levels of the two excipients are as shown in Table 13 below. Table 13 Excipient Concentration of excipient Saturation solubility of enavogliflozin (mg/mL) Polyoxyl 40 stearate 7.0 w/v% 32.01 Kolliphor TM EL 5.0 w/v% 16.84
• polyoxyl 40 stearate can solubilize enavogliflozin about twice as much as Kolliphor TM EL.
• Kolliphor TM EL was changed to polyoxyl 40 stearate to prepare the formulations of Formulation-6, Formulation-7, and Formulation-8.
• the appearance, content, pH, osmolality, and cloud point thereof were evaluated.
• the cloud point of the formulation of Formulation-1 was measured. The results are shown in Table 14 below.
• the eye drop formulations were prepared using the same method as (3-1) of Example 1 according to the components and amounts of Table 16, with the active ingredient in the concentration of 2.0 w/v%.
• Table 16 Raw material Formulation-9 (Active ingredient: 2.0 w/v%) Formulation-10 (Active ingredient: 2.0 w/v%) Amount (mg/mL) Amount (mg/mL) Active ingredient Enavogliflozin 20.0 20.0 Surfactant Tween TM 80 20.0 20.0 Surfactant Kolliphor TM EL 40.0 - Surfactant Polyoxyl 40 stearate - 70.0
• each formulation was administered to 10 animals. After the rats were stabilized outside the cage, the upper eyelid and the lower eyelid were opened and 5 ⁇ L of each test formulation was instilled into each of the right and left eyes using a pipette. The rats were maintained for a certain period of time so as not to flow out after the instillations. At the sampling time points corresponding to 1, 2, 4, 6, and 12 hours after the instillations, each two rats were inhaled-anesthetized with isoflurane and the left and right eyes were extracted using surgical scissors and forceps. The retinal tissues isolated from the left and right eyes were collected into a 1.5 mL Eppendorf tube immediately after the isolation.
• the intraocular drug concentration profiles obtained by performing the pharmacodynamic study in rat eyes as described above are as shown in FIG. 4 .
• the eye drop formulation obtained by using polyoxyl 40 stearate according to the present invention maintained a significantly higher intraocular concentration. Therefore, the eye drop formulation obtained according to the present invention can increase the intraocular exposure of enavogliflozin, thereby providing excellent pharmacological activity.

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